Psychoactive substances vary considerably in their abuse liability from those such as major tranquilizers in which self-administration is difficult to sustain to smokable forms of cocaine which are highly addictive. Quantitation of the differences and discovering the mechanisms which underly the differences is fundamental to the development of safer medications in general, as well as for the development of more effective medications for treating addiction. Two strategies for human evaluation of the mechanisms of drug abuse liability are drug discrimination and drug self-administration. Both of these paradigms evolved from animal research and their application to humans makes it possible to apply animal and human data to identify mechanisms of addiction. Presently we are using the drug discrimination paradigm to explore the mechanisms which confer a high abuse liability upon stimulants such as amphetamine, whereas stimulants such as caffeine are of substantially lower abuse liability. In a series of three studies, the subjective and discriminative effects of several stimulant drugs are being investigated that are widely sold via mail order and designed to imitate amphetamine- like stimulants. These so called "look-alike" stimulants contain caffeine alone or combined with one or more sympathomimetic amines, such as ephedrine and phenylpropanolamine (PPA). Little is known about the behavioral pharmacology in humans of the combined effects of these drugs, including effects when individuals exceed the therapeutic dosage in an attempt to achieve amphetamine-like euphoria. These studies, which are in progress, are investigating the drugs both singly and in combination. Another series of studies, in progress, is aimed at refining the drug self-administration paradigm presently used to enable more systematic evaluation of the reinforcing effects of opioids. This study of opioid self-administration will then be extended to evaluate the role of behavioral factors as modulators of the reinforcing effects of the drugs.